U.S. patent number 7,091,194 [Application Number 09/979,533] was granted by the patent office on 2006-08-15 for method for increasing the production of propionate in the gastrointestinal tract.
This patent grant is currently assigned to Nestec S.A.. Invention is credited to Eva Arrigoni, Anne Bauche, Alfred Jann, Florence Rochat, Daniel Schmid.
United States Patent |
7,091,194 |
Jann , et al. |
August 15, 2006 |
Method for increasing the production of propionate in the
gastrointestinal tract
Abstract
A method for selectively increasing the production of propionate
in the gastro-intestinal tract of a mammal. The method includes the
step of enterally administering to the mammal a nutritional
composition which contains dextran. Increasing the propionate
production results in decreased blood cholesterol levels, decreased
blood triglyceride levels, decreased very low density lipoprotein
levels, increased high density lipoprotein levels, and increased
insulin sensitivity.
Inventors: |
Jann; Alfred (Publier,
CH), Arrigoni; Eva (Thalwil, CH), Rochat;
Florence (Montreux, CH), Schmid; Daniel
(Lausanne, CH), Bauche; Anne (Lausanne,
FR) |
Assignee: |
Nestec S.A. (Vevey,
CH)
|
Family
ID: |
8238212 |
Appl.
No.: |
09/979,533 |
Filed: |
May 19, 2000 |
PCT
Filed: |
May 19, 2000 |
PCT No.: |
PCT/EP00/04744 |
371(c)(1),(2),(4) Date: |
March 08, 2002 |
PCT
Pub. No.: |
WO00/70964 |
PCT
Pub. Date: |
November 30, 2000 |
Foreign Application Priority Data
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May 20, 1999 [EP] |
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99109916 |
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Current U.S.
Class: |
514/59; 426/139;
426/310; 426/548; 426/579 |
Current CPC
Class: |
A61K
31/721 (20130101); A23L 29/273 (20160801); A23L
33/12 (20160801); A23L 33/21 (20160801) |
Current International
Class: |
A23L
1/054 (20060101) |
Field of
Search: |
;426/579,548,139,310
;514/59 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 153 013 |
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Aug 1985 |
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EP |
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0 382 355 |
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Aug 1990 |
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EP |
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0 881 283 |
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Dec 1998 |
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EP |
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60-190717 |
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Sep 1985 |
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JP |
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Other References
"Pharmaceutical Aspects of Dietary Fibre" by Professor N.W. Read.
"Dietary Fructans", Roberfroid et al., Annu. Rev. Nutr., 1998, vol.
18, pp. 117-143. cited by other .
"Dietary Fructans", Roberfroid et al., Annu. Rev. Nutr., 1998, vol.
18, pp. 117-143. cited by other.
|
Primary Examiner: Marx; Irene
Attorney, Agent or Firm: Bell, Boyd & Lloyd LLC
Claims
The invention claimed is:
1. A method for increasing production of propionate in a
gastro-intestinal tract of a mammal by orally administering a
nutritional composition comprising dextran having a molecular
weight of about 2,000,000 wherein dextran is administered in an
amount from about 10 g per day to about 15 g per day.
2. The method according to claim 1 wherein the nutritional
composition further comprises at least one component selected from
the group consisting of inulin, fructo-oligosaccharide,
galacto-oligosaccharides, xylo-oligosaccharides, and a mixture
thereof.
3. The method according to claim 1 wherein the nutritional
composition further comprises a lipid source that includes a
monounsaturated fatty acid and a saturated fatty acid and wherein
the monounsaturated fatty acid provides at least 50% of energy of
the lipid source and the saturated fatty acid provides less than
20% of energy of the lipid source.
Description
FIELD OF THE INVENTION
This invention relates to a method for preferentially increasing
the synthesis of propionate in the gastrointestinal tract by
administering dextran. The invention also relates to methods for
the nutritional management of blood cholesterol levels, blood
triglyceride levels, blood lipoprotein levels, and insulin
sensitivity by administering dextran.
BACKGROUND TO THE INVENTION
Certain non-digestible polysaccharides, which are often termed
prebiotic fibres, are fermented by micro-organisms in the
gastrointestinal tract. Examples of these polysaccharides are
inulin and its hydrolysis products. The products of the
fermentation lead to the provision of energy, the selective
stimulation of growth of lactic acid bacteria and the regulation of
cellular metabolism. One class of these fermentation products are
the short chain fatty acids acetate, propionate and butyrate.
Of the short chain fatty acids, propionate is thought to (i)
mediate the reduced hepatic gluconeogenesis induced by
non-digestible polysaccharides, (ii) inhibit gluconeogenesis in the
liver, (iii) enhance glycolysis, (iv) lower plasma fatty acid
concentrations, (v) inhibit ureagenesis in the liver, and (v)
increase insulin sensitivity (Roberfroid et al; 1998; Annu. Rev.
Nutr.; 18:117 43). Acetate, however, increases plasma fatty acid
concentrations (Roberfroid et al; 1998; Annu. Rev. Nutr.; 18:117
43).
The selective production of propionate in the gastrointestinal
tract would therefore be of benefit in the nutritional management
of many conditions. However, the primary fatty acid which is
produced upon fermentation of known non-digestible polysaccharides
is acetate, followed by butyrate and propionate. Hence these
non-digestible polysaccharides are not suitable for selectively
increasing the production of propionate in the gastrointestinal
tract.
Therefore, it is an object of this invention to provide a method
for selectively increasing the production of propionate in the
gastro-intestinal tract.
SUMMARY OF THE INVENTION
Accordingly, in one aspect, this invention provides a method for
selectively increasing the production of propionate in the
gastrointestinal tract, the method comprising enterally
administering to a mammal a nutritional composition which contains
dextran.
It has been surprisingly found that dextran, when fermented by
micro-organisms which occur in the gastrointestinal tract, results
in the increased production of propionate when compared to other
non-digestible polysaccharides. Therefore, dextran is an ideal
source of propionate in the gastro-intestinal tract.
The term "dextran" means a group of polysaccharide which are
composed of .alpha.-D-glucopyranosyl units linked predominantly
.alpha.-D(1.fwdarw.6). Dextrans are produced by certain types
bacteria growing on a glucose substrate; for example Leuconostoc
mesenteroides, Leuconostoc dextranicum, and Leuconostoc
mesenteroides ssp. cremoris. Further, shorter chain dextrans may be
obtained by hydrolysing native dextrans or by synthesising
them.
In another aspect, this invention provides a method for decreasing
blood cholesterol levels in a mammal, the method comprising
enterally administering to a mammal a nutritional composition which
contains dextran.
In another aspect, this invention provides a method for decreasing
blood triglyceride levels in a mammal, the method comprising
enterally administering to a mammal a nutritional composition which
contains dextran.
In another aspect, this invention provides a method for decreasing
very low density lipoprotein levels in a mammal, the method
comprising enterally administering to a mammal a nutritional
composition which contains dextran.
In another aspect, this invention provides a method for increasing
high density lipoprotein levels in a mammal, the method comprising
enterally administering to a mammal a nutritional composition which
contains dextran.
In another aspect, this invention provides a method for increasing
insulin sensitivity in a mammal, the method comprising enterally
administering to a mammal a nutritional composition which contains
dextran.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Embodiments of the invention are now described, by way of example
only.
This invention is based upon the discovery that the colonic
fermentation of dextran by micro-organisms results in the
production of relatively larger amounts of propionate as compared
to other non-digestible polysaccharides. Therefore, the enteral
administration of dextran provides a convenient and simple way of
selectively increasing the production of propionate in the
gastro-intestinal tract.
The dextran used may be any suitable dextran; natural, synthetic or
partially hydrolysed. Suitable dextrans are commercially available
or may be produced by growing Leuconostoc micro-organisms on a
sucrose substrate and isolating and purifying the dextran.
Alternatively, the dextran may be produced as described in European
patent application 0881283.
Preferably, however, the dextran is a high molecular weight
dextran; for example having a molecular weight above 50000,
preferably above about 70000, more preferably above about 100000;
for example above about 500000.
The dextran may be formulated into any suitable nutritional
composition as desired since the exact composition and form is not
critical. One suitable class of nutritional compositions is food
products. Examples of suitable food products include yoghurts, ice
cream confections, milk-based drinks, salad dressings, sauces,
toppings, desserts, confectionery products, biscuits, cereal-based
snack bars, prepared dishes, and the like. For humans, food
products which are convenience foods are preferred since patient
compliance is increased. Another suitable class of nutritional
compositions is nutritional formulas such as enteral formulas for
clinical and infant nutrition, and nutritional supplements. For
pets, the nutritional compositions may be in the form of pet foods
such as dried kibbles and retorted wet products.
The nutritional compositions may contain other ingredients as
desired. For example, the nutritional compositions may contain
other polysaccharides such as insoluble and soluble fibres. Fibres
are known to have a beneficial effect upon cholesterol and glucose
levels. Suitable sources of soluble and insoluble fibres are
commercially available.
An example of a suitable fibre is inulin or its hydrolysis
products. The inulin may be provided in the form of a natural
extract which is suitable for human consumption. Suitable inulin
extracts may be obtained from Oraffi SA of Tirlemont 3300, Belgium
under the trade mark "Raftiline". For example, the inulin may be
provided in the form of Raftiline.RTM.ST which is a fine white
powder which contains about 90 to about 94% by weight of inulin, up
to about 4% by weight of glucose and fructose, and about 4 to 9% by
weight of sucrose. The average degree of polymerisation of the
inulin is about 10 to about 12. The hydrolysis products of inulin
are fructo-oligosaccharides in the form of fructose oligomers
containing 1-kestose(GF2), nystose(GF3), and 1F-fructofuranosyl
nystose(GF4), in which fructosyl units(F) are bound at the
.beta.-2,1 position of sucrose(GF) respectively. The
fructo-oligosaccharides may be obtained commercially, for example
from Orafti SA of Tirlemont 3300, Belgium under the trade mark
"Raftilose", or from Meiji Seika Co. of Japan. For example, the
fructo-oligosaccharides may be provided in the form of
Raftilose.RTM.P95. Other oligosaccharides may be included if
desired. Suitable examples are galacto-oligosaccarides,
xylo-oligosaccharides or oligo derivatives of starch.
If both soluble and insoluble fibre are used, the ratio of soluble
fibre to insoluble fibre is preferably about 1:3 to about 3:1; more
preferably about 1:1 to about 2:1.
The nutritional composition may also contain vitamins and minerals
as desired. For clinical applications, the nutritional composition
preferably includes a complete vitamin and mineral profile. For
example, sufficient vitamins and minerals may be provided to supply
about 25% to about 250% of the recommended daily allowance of the
vitamins and minerals per 1000 calories of the nutritional
composition.
When the nutritional composition is in the form of a food product
or nutritional formula, the nutritional composition may contain a
protein source, a lipid source and a carbohydrate source. These
sources may be selected as desired.
The lipid source is preferably rich in monounsaturated fatty acids;
for example monounsaturated fatty acids may provide at least 50% of
energy of the lipid source. The lipid source may also contain
polyunsaturated fatty acids (omega-3 and omega-6 fatty acids). The
lipid profile is preferably designed to have a polyunsaturated
fatty acid omega-6 (n-6) to omega-3 (n-3) ratio of about 4:1 to
about 10:1. Saturated fatty acids preferably provide less than 20%
of the energy of the lipid source; for example less than about
15%.
The nutritional composition may be used in the nutritional
management of conditions such as diabetes and
hypercholesterolemia.
The amount of the nutritional composition required to be fed to a
patient will vary depending upon factors such as the patient's
condition, the patient's body weight, the age of the patient, and
whether the nutritional composition is the sole source of
nutrition. However the required amount may be readily set by a
medical practitioner. In general, sufficient of the nutritional
composition is administered to provide the patient with up to about
40 g of dietary fibre (insoluble and soluble) per day; for example
about 25 g to about 35 g of dietary fibre per day. The amount of
dextran that the patient receives is preferably in the range of
about 2 g to about 15 g per day. If the nutritional formula is used
as a supplement to other foods, the amount of the nutritional
composition that is administered daily may be decreased
accordingly.
The nutritional composition may be taken in multiple doses, for
example 2 to 5 times, to make up the required daily amount or may
taken in a single dose. The nutritional composition may also be fed
continuously over a desired period.
The invention is now further described with reference to the
following specific examples.
EXAMPLE 1
Three non-digestible polysaccharides are fermented in an in vitro
fermentation model which simulates fermentation conditions in the
gastro-intestinal tract. The polysaccharides are (i) acacia gum
(available under the trade name Fibregum), (ii) Dextran produced
according to European patent application 0881283, and (iii)
lactulose.
For each polysaccharide, an amount of 100 mg of the polysaccharide
is added to 8 ml of a carbonate-phosphate buffer, which contains
oligo-elements, in a 50 ml air-tight flask. The composition of the
buffer is as follows:--
TABLE-US-00001 Component Amount NaHCO.sub.3 9.240 g/l
Na.sub.2HPO.sub.4.12H.sub.2O 7.125 g/l NaCl 0.470 g/l KCl 0.450 g/l
Urea 0.400 g/l CaCl.sub.2.6H.sub.2O 0.108 g/l Na.sub.2SO.sub.4
0.100 g/l MgCl.sub.2.6H.sub.2O 0.100 g/l FeSO.sub.4.7H.sub.2O 36.80
mg/l MnSO.sub.4.H.sub.2O 11.59 mg/l ZnSO.sub.4.7H.sub.2O 4.40 mg/l
CoCl.sub.2.6H.sub.2O 1.20 mg/l NiCl.sub.2 1.00 mg/l
CuSO.sub.4.5H.sub.2O 0.98 mg/l
Mo.sub.7(NH.sub.4).sub.6O.sub.24.4H.sub.2O 0.17 mg/l Resazurine
1.00 mg/l
Each flask is rinced for 1 minute with CO.sub.2 gas and stored at
4.degree. C. for 16 hours under a slight over-pressure.
Dilute human faeces is prepared from samples of fresh faeces
collected from healthy humans not having consumed antibiotics for
at least 3 months and not producing methane. The faeces are
immediately rinced with CO.sub.2 gas, and 3 parts (weight/weight)
of the carbonate-phosphate buffer with oligo-elements are rapidly
added at 37.degree. C. The mixture is blended for 2 minutes in a
stomacher (Stomacher 400, Seward, London, GB) and filtered by a
Polymon PES1000/45 filter with 1 mm holes (Schweizerische
Seidenfabrik SA, Zurich, CH).
An amount of 2 ml of the dilute faeces is added to each flask and
the head space gas is replaced by a flux of temperate CO.sub.2 gas
for 1 minute. After equilibration of the pressure, each flask is
sealed air-tight and incubated in an agitated water bath at
37.degree. C.
After 24 hours, the content of short chain fatty acids in the
flasks determined twice by direct injection of an acidified and
sterile filtered sample on a gas chromatograph with FID (HP 8960,
Hewlett Packard, Urdorf, CH) fitted with a DB-FFAP capillary column
(MSP FRIEDLI & Co, Koeniz, CH). The results are as
follows:--
TABLE-US-00002 Short Chain SCFA Content Polysaccharide fatty acid
(.mu.mol/100 mg) SCFA % of total* Fibregum Acetate 648.2 63.7
Propionate 228.6 22.5 Butyrate 107.1 10.5 Dextran Acetate 415.0
46.3 Propionate 363.5 40.6 Butyrate 87.6 9.8 Lactulose Acetate
909.2 74.6 Propionate 111.7 9.2 Butyrate 172.2 14.1 *the
percentages do not added up to 100% since other short chain fatty
acids are present in minor amounts.
The results indicate that fermentation of dextran results in
increased production of propionate; relatively and absolutely. For
the other polysaccharides, only acetate was favoured.
EXAMPLE 2
A study is undertaken with 45 mice aged between 7 and 10 weeks. The
mice are kept in sterile conditions in cages. The mice have free
access to water and a standard diet.
On the first day of the study, each mouse is fed 0.5 ml of a
complete human microbial flora, diluted 100 times, by intra-gastric
tube. The feeding is repeated on day 2. On day 11, the mice are
separated into three groups; each group being housed in a separate
sterile isolation unit.
On day 15, each group of mice receives a test diet. The test diets
are sterile. The test diets all contain a potato puree, sugar, fish
meal, cellulose, vitamins and minerals and a non-digestible
polysaccharide. The polysaccharides are as follows:--
TABLE-US-00003 Diet Polysaccharide Positive Control
Fructo-oligosaccharide (Raftilose) Negative Control Cellulose Diet
1 Dextran
The mice are fed the diets until day 36. During this time, the
development of the intestinal flora of each mouse is monitored by
collecting faeces and determining microbial counts. A blood sample
is collected from each mouse and analysed for short chain fatty
acids. The mice are then anaesthetised and sacrificed. The caecum
and stomach contents of each mouse is removed and analysed for
short chain fatty acids and microbial flora, respectively.
All mice fed Diet 1 have relatively higher levels of propionate in
the blood and caecum.
EXAMPLE 3
A study was performed to evaluate with 3 to 5 volunteers whether a
significant increase of propionic acid could be meausred in feces
after consumption of an acute dose of 15 g Dextran T2000 and a
chronic dose of 10 g Dextran T2000 per day.
This study was performed as a randomiszed placebo-controlled double
blind study with 4 volunteers in a cross-over design. SCFAs were
measured in feces. Additionally, blood formula and selected blood
proteins were measured before and after consumption of the
dextran.
Outline of Results
a) the effect of an accute dose of 15 g dextran on propionic acid
in feces was investigated. The pool of feces collected between 12
and 72 hours after consumption of the acute does was analysed for
short chain fatty acids (SCFAs). Taking the average results of the
4 volunteers, propionic acid infeces of the pool increased by 3.43
mmol in the treatmetn group relative to the placebo group. b) a
chronic consumption of 10 g dextran per day was investigated.
Propionic caid concentration in a fecal sample was analysed after 1
week of chronic consumption. Taking the average of the 4
volunteers, propionic acid concentration increased by 24.0
.mu.mol/g dry feces in the treatment group compared to a decrease
of 5.7 lmol/g dry feces in the placebo group.
Consumption of dextran induced no relevant changes of blood
formula, investigated blood proteins or blood plasma enzymes. No
clinical symptoms have been reported.
Conclusions
The results indicate an increase in the level of propionic acid in
the gastro-intestinal tract following consumption of dextran.
Results
A summary of results from the study on dextran is set out below.
This was a placebo controlled double blind study with a cross-over
design. 4 volunteers were enrolled.
Results are given separately for treatment (Dextran) and placebo
(maltodextrin). Additionally results relative to placebo are
given.
TABLE-US-00004 fecal samples (1 week intake of 10 g per day) C2:
acetic acid C3: propionic acid volunteer pionate conc. C3/C2 %
propionic acid In average: Treatment 1 89.89 -0.139 0.1 2 -13.73
-0.087 -2.7 3 1.31 0.071 6.8 During treatment, propionate
concentration increased by 24.0 .mu.mol/g dry feces. 4 18.43 0.007
3.3 During treatment, propionate/acetate ratio decreased by 0.04.
av 23.98 .mu.mol/g dry -0.037 1.9 During treatment, % age of
propionate on total SCFAs increased by 1.9%. Placebo 1 11.39 -0.027
-0.7 2 -2.35 -0.144 -4.6 3 -27.51 -0.041 -0.9 During placebo,
propionate concentration decreased by 5.7 .mu.mol/g dry feces. 4
-4.36 -0.002 -0.2 During placebo, propionate/acetate ratio
decreased by 0.05. av -5.71 .mu.mol/g dry -0.054 -1.6 During
placebo, % age of propionate on total SCFAs decreased by 1.6%.
treatm - plac. 1 78.50 -0.112 0.8 2 -11.38 0.057 1.9 3 28.82 0.112
7.7 Relative to placebo, propionate concentration increased by 29.7
.mu.mol/g dry feces. 4 22.79 0.009 3.5 Relative to placebo,
propionate/acetate ration increased by 0.02. av 29.68 .mu.mol/g dr
0.02 3.5 Relative to placebo, % age of propionate on total SCFAs
increased by 3.5%.
TABLE-US-00005 p ol of feces (12h to 72h after intake of 15 g) In
blood, no changes in SCFA concentrations were observed. C3 produce
C3 in tot C3/C2 conc. C3 (.mu.mol/g wet) In average: treatment 1
29.65 30.32 0.57 35.54 2 2.26 20.98 0.39 8.61 During treatment,
propionate production was 10.8 mmol. 3 8.41 22.31 0.47 35.86 During
treatment, % age of propionate on total SCFAs was 23%. 4 2.91 18.20
0.34 13.88 During treatment, propionate by acetate ratio 0.44. av
10.81 22.95 0.44 23.47 During treatment, propionate concentration
was 23.5 .mu.mol/g wet feces. placebo 1 17.11 24.84 0.44 26.84 2
3.91 18.13 0.35 11.97 During treatment, propionate production was
7.4 mmol. 3 4.46 22.37 0.48 22.96 During treatment, % age of
propionate on total SCFAs was 20.4%. 4 4.04 16.39 0.27 10.35 During
treatment, propionate by acetate ratio 0.39. av 7.38 20.43 0.39
18.03 During treatment, propionate concentration was 18.0 .mu.mol/g
wet feces. treatment - placebo 1 12.54 5.48 0.13 8.69 2 -1.65 2.84
0.04 -3.37 Relative to placebo, propionate production was 3.4 mmol.
3 3.95 -0.06 -0.01 12.90 Relative to placebo, % age of propionate
on total SCFAs was 2.5%. 4 -1.12 1.81 0.06 3.53 Relative to
placebo, propionate/acetate ration increased by 0.06 (or 15%). av
3.43 2.52 0.06 5.44 Relative to placebo, propionate concentration
increased by 5.4 .mu.mol/g wet feces. (=+15%)
* * * * *